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16/17/18 - Diuretics Flashcards

1
Q

Which DIURETIC?

A
  • *BUMETANIDE**
  • *LOOP DIURETIC**

40-50x more potent than furosemide

Sulfonamide moiety
in furosemide and bumetanide also
provides weak CA inhibitory activity, thus
increase phosphate and bicarbonate excretion.

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2
Q

Which Diuretic causes this side effect?

“Contraction” Alkalosis

A

LOOP DIURETICS
Furosemide, Bumetanide, Torsemide, Ethacrinic Acid

Due to:
Significant diuresis can lead to hypovolemia ‐> stimulation of Aldosterone ‐> H+ excretion

Also:
HypoCalcemia*** // ***HypoMagnesemia
Ototoxicity // GOUT
Mild - HYPERglycemia / increase in Cholesterol / TG’s

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3
Q

Edema Treatment

A

Mainstay of therapy is:
NaCl RESTRICTION
diuretics will NOT work if the increased loss is REPLACED by MORE NACL INTAKE
Restriction depends on degree of edema:
SEVERE EDEMA: <1gm NaCl per day

  • *Loop Diuretics are 1st line after**
  • *daily dosing** –> increase dose or BID
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4
Q

Which DIURETIC?

A

Dichlorfenamide​
META-disulfamoylbenzene derivatives

Carbonic Anhydrase Inhibitor

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5
Q

Which DIURETIC?

A
  • *FUROSEMIDE**
  • *LOOP DIURETIC**

Sulfonamide moiety
in furosemide and bumetanide also
provides weak CA inhibitory activity, thus
increase phosphate and bicarbonate excretion.

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6
Q

Which Diuretic?

A
  • *Acetazolamide**
  • *SIMPLE heterocyclic sulfonamides**

Carbonic Anhydrase Inhibitor

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7
Q

Which Diuretic causes this side effect?

METABOLIC ACIDOSIS

A

CAIs
Acetazolamide + Methazolamide (Simple)
Dichlorfenamide + Dorzolamide (meta)

HCO3 is indirectly REABSORBED by CA
VVV
Blocking CA –> less HCO3 reabsorbed // more EXCRETED
VVV
METABOLIC ACIDOSIS

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8
Q

Which Diuretic causes this side effect?

HypoCalcemia

A

LOOP DIURETICS
•Furosemide, Bumetanide, Torsemide, Ethacrinic Acid

Also:
HypoKalemia // HypoMagnesemia
Ototoxicity // GOUT // Contaction ALKAlosis
Mild - HYPERglycemia / increase in Cholesterol / TG’s

Also used for:
Severe HYPERcalcemia
but MAINLY EDEMA
not proven to be good for HYPERtension

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9
Q

Which Diuretic causes this side effect?

HypoNatremia

A

THIAZIDE DIURETICS

Also:
HYPERcalcemia
HypoKalemia*** / ***HypoMagnesemia / GOUT
and MILD:
HyperGlycemia // TG // Cholesterol

INEFFECTIVE @ CrCl <30 mL/min
need RENAL function

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10
Q

What occurs in the ASCENDING LIMB?

Urine Formation

A
  • *“Dilution of Luminal Fluid”**
  • water IMpermeable*

RE-absorption of NaCl
30% of filtered Na+ –> reenters

Para-cellular Transport
used to compensate for HIGH Na+

  • *Symporter_ + _Antiporter**
  • *ATPase**
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11
Q

Which Diuretic is indicated for:
DECREASED MORTALITY**in**HFrEF
heart failure w/ reduced ejection fraction

A

Aldosterone Antagonist
Spironolactone & Eplerenone
K+ sparing Diuretics, weak diuretic

Other indications:
Combo w/ HCTZ to prevent hypokalemia

Hepatic Cirrhosis w/ ascites

Resistant Hypertension

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12
Q

2-Step Concentration Process
of
Renal Tubular Secretion
(1 of 2 ways to enter into the luminal fluid, Glomerular Filtration is the other)

A

@PROXIMAL TUBULE

1) Active Secretion, interstitium –> proximal tubule
via OATS / OCTS
most diuretics are either weak organic acids or weak organic bases
important for GOUT –> URIC ACID competes with DIURETICS

2) Passive + Active Transport, Proximal Tubule –> Luminal Fluid
of diuretics

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13
Q

Which DIURETIC?

A

SORBITOL

Osmotic Diuretic

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14
Q

Which DIURETIC, based on MECHANISM OF ACTION?

  • Inhibition of*
  • *Renal Carbonic Anhydrase**
  • decreases the:*
  • *Sodium Carbonate Reabsorption**
A

Carbonic Anhydrase Inhibitors
CAI

Acetazolamide + Methazolamide
(Simple)
&
Dichlorfenamide + Dorzolamide
(meta)

Act on:
Proximal Tubule

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15
Q

Which DIURETIC?

A

MANNITOL
Isomer of SORBITOL

Osmotic Diuretics

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16
Q

Which DIURETIC?

A
  • *TORSEMIDE**
  • *Loop Diuretic**
  • *sulfonylurea lacking an unsubstituted sulfamoyl group,**
  • does not act at the proximal tubule*
  • therefore does NOT increase phosphate or bicarbonate excretion.*

= no CA activity

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17
Q

Which Diuretic causes this side effect?

HYPERkalemia

A

K+ Sparing Diuretics

–Requires regular monitoring – can cause fatal arrhythmias
Risk increases greatly with CrCl < 50
Discontinue if K > 5.0 or CrCl < 30
Use in patients on dialysis is controversial in patients with HFrEF

Spironololactone also:
GYNECOMASTIA

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18
Q

What occurs in the COLLECTING DUCT?

Urine Formation

A

Re-Absorption of Water

  • *Reabsorption & Secretion of**
  • *Na / K / H / HCO3**

Na+/K+ ATPase
driving force for re-absprotion

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19
Q
  • *What conditions cause a
  • Diminished response to LOOP DIURETICS?***
A

Renal Insufficiency / Nephrotic Syndrome

Heart Failure / Cirrhosis

  • may require
  • HIGHER DOSES –> reach ceiling/max effect**

Ceiling dose:

  • *80-160mg** for Furosemide
  • *1-2 mg** for Bumetanide
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20
Q

How does the nephron REACT to HYPOVOLEMIA?

Reduced Plasma Volume or Dehydration

A

↓Renal Blood flow
↓GFR

↑Renin Secretion

↑Antidiuretic Hormone
increase in water RE-absorption

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21
Q

Which DIURETIC?

A
  • *ETHCRYNIC ACID_ + _INDACRINONE**
  • *Phenoxyacetic Acid-type High Ceiling Diuretics**

In addition to inhibit ATPase;
it also blocks the luminal Na+/K+/2Cl- co- transporter similar to furosemide

no sulfonamide group = does NOT inhibit CAI

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22
Q

Which DIURETIC?

A
  • *EPLERENONE**
  • *K+ Sparing Diuretic**

Aldosterone Receptor Agonist

Eplerenone, a newer aldosterone receptor antagonist with better ADH receptor selectivity than spironolactone.

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23
Q

What can NOT be taken with a LOOP DIURETIC?

A

THIAZIDE DIURETICS

CAN NOT BE TAKEN WITH LOOP DIURETICS

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24
Q

What group on Thiazide Diuretics is associated with:

HyperSensitivity Rxns / Drug-Induced Fever

Blood Dyscrasias / Interstitial Nephritis

Cross Sensitivity with CAI’s
+ loop diuretics or antibiotics with this group

A

SULFAMOYL MOIETY
SO2NH2

Thiazide Diuretics also have ADR of:
HypoKalemia

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25
Q

Which DIURETIC acts on:

EARLY DISTAL TUBULE

A

THIAZIDE DIURETICS

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26
Q

Which DIURETIC acts on:

THICK ASCENDING LIMB

A

LOOP DIURETICS
Furosemide / Bumetanide / Torsemide

27
Q

Which DIURETIC, based on MECHANISM OF ACTION?

Sodium and water reabsorption decreases
because of
reduced medullary hyper tonicity
and
elevated urinary flow rate

A

OSMOTIC DIURETIC

Mannitol / Isosorbide / Sorbitol

Act on:
Proximal Tubule
&
Descending Limb

28
Q

Indication for these K+ Sparing Diuretics:

Sodium Channel Blockers
(of Collecting Ducts)
Triamterene / Amiloride

A

very weak diuretics

Often used in:
COMBO with HCTZ to PREVENT HypoKalemia

29
Q

Which DIURETIC, based on MECHANISM OF ACTION?

  • INHIBITION OF*
  • *Na+ - Cl- Symporter**
A

THIAZIDES + Thiazide -like

All Thiazides also have CA inhibition!

Act at the:
beginning of the DISTAL TUBULE

30
Q

Which DIURETIC?

A
  • *Dorzolamide**
  • *META-disulfamoylbenzene derivatives**

Carbonic Anhydrase Inhibitor

31
Q

Benzothiazide (Thiazide) Diuretics

Which is ESSENTIAL FOR DIURETIC ACTIVITY?

A

Sulfonamide** @ **C-7
is essential for diuretic Activity

EWG** @ **C-6
is needed for diuretic activity

32
Q

Benzothiazide (Thiazide) Diuretics

What can only TOLERATE a METHYL GROUP?

&

What can be REPLACED?

Carbonyl containing groups can replace the sulfonamide group at S-1 and N-2.

A

N-2
can only tolerate a methyl group
will stop the THIAZIDE DIURETIC effect, but not CAI

Carbonyl-containing groups** –> **Sulfonamide
at S-1** & **N-2
can replace sulfonamide with no problem

33
Q

Which DIURETIC?

A
  • *AMILORIDE**
  • *K+ Sparing Diuretic**

SELECTIVE SODIUM CHANNEL BLOCKER

Highly Basic

amiloride is excreted unchanged since it is not further metabolized

34
Q

How do Thiazide Diurteics / Loop Diuretics cause

HypoKalemia?

A

In the Collecting Duct:
Increased Na+ Concentration in Urine
VV
Increased K+ Secretion into Urine
VVV
K+ Is released with the urine

“Na+ back IN –> K+ OUT”

35
Q

Which DIURETIC acts on:

LATE DISTAL TUBULE + COLLECTING DUCT

A

POTASSIUM SPARING DIURETICS

SPIRONOLACTONE
Aldosterone / Canrenone / Eplerenone

TRIAMTERENE & AMILORIDE

36
Q

What occurs in the:
PROXIMAL TUBULE?

Urine Formation

A

REABSORPTION –> into blood
Glucose / Vitamins / AA / NaCl / HC03 / K / WATER

  • *Transcellular Re-Absorption** by CA (carbonanhydrase)
  • *Na+ / HCO3**
  • passive processes:*
  • *Transcellular Transport of**
  • *Na+** coupled to Glucose / AA / Phosphate
  • *PARAcellular Transport of**
  • *Na+ / Cl-**
  • through the INTERcellular space*
37
Q

Causes of Edema

A

Increased Capillary Hydraulic Pressure
due to liver or heart failure

HypoALBUMINemia
due to nephrotic syndrome / malnutrition

Increased Capillary Permeability
due to massive INFLAMMATORY states = burn patients

Lymphedema
lymphatic obstruction

38
Q

Which DIURETIC?

A

SPIRONOLACTONE –> Canerone
Canerone = major active metabolite

K+ Sparing Diuretic

ALDOSTERONE RECEPTOR AGONIST

synthetic steroid that blocks aldosterone receptors –> less Na+/K+ ATPase
in the later distal tubule and collecting duct

39
Q

Indication for:
OSMOTIC DIURETICS

A

ELEVATED INTRACRANIAL PRESSURE

  • *Given IV**
  • does NOT penetrate BBB*

Once filtered, cannot be reabsorbed –> pulls fluid into tubules for excretion

40
Q

Which Diuretic is Indicated for:

Prophylaxis of ACUTE ALTITUDE SICKNESS?

A

CAIs
Acetazolamide + Methazolamide (Simple)
Dichlorfenamide + Dorzolamide (meta)

Also for:
GLAUCOMA

41
Q

Which Diuretic causes this side effect?

HYPERcalcemia

A

THIAZIDE DIURETICS

Also:
HypoNatremia
HypoKalemia*** / ***HypoMagnesemia / GOUT
and MILD:
HyperGlycemia // TG // Cholesterol

INEFFECTIVE @ CrCl <30 mL/min
need RENAL function

42
Q

Which Loop Diuretic

does NOT have CA inhibitory Activity?

A

TORSEMIDE

does NOT have a
Sulfonamide Moiety

  • does NOT increase
  • Phos // Bicarb excretion**

Furosemide / Bumetanide does

43
Q

Phenoxyacetic Acid-Type
High Ceiling Diuretics

MoA / Target

A

Etacrynic Acid** + **Indacrinone

Target:
Thick Ascending Limb

Inhibits BOTH:
ATPase
Luminal Na/K/Cl- Co-Transporter
(similar to furosemide)

44
Q

Which Diuretic causes this side effect?

GOUT

A

LOOP DIURETICS
Furosemide, Bumetanide, Torsemide, Ethacrinic Acid

THIAZIDE DIURETICS

Compete for elmination with:
OATs
VVV
ACCUMULATION OF URIC ACID

45
Q

Which DIURETIC?

A

Benzothiazide (Thiazide) Diuretics

46
Q

What occurs in the DISTAL TUBULE?

Urine Formation

A
  • *Secretion: Ammonia / Uric Acid / Penicillin**
  • some WATER RE-absorption*

Symporter
Reabsorption of NaCl –> epithelium

Na+/ K+ ATPase
driving force for Re-absorption of Na –> Blood

47
Q

Which Diuretic?

Indication:
Mainly as ANTI-HYPERTENSIVE, not as diuretic

CI:
INEFFECTIVE @ CrCl < 30 mL/min

A

Thiazide Diuretics
HCTZ / Chlorthalidone
Metolazone / Indapamide

Cause:
HypoNatremia
HypoKalemia // HypoMag
HYPERcalcemia / HYPERuricemia

48
Q

Which DIURETIC, based on MECHANISM OF ACTION?

Inhibition of Na+ & Water RE-absorption by:

  • *Competitive Inhibition of Aldosterone Receptor**
  • *“MineralCorticoid Receptor”**
A

POTASSIUM SPARING DIURETIC

SPIRONOLACTIONE
Aldosterone / Canrenone / Eplerenone

Act on:
late DISTAL TUBULE + COLLECTING DUCT

49
Q

Benzothiazide (Thiazide) Diuretics

  • *What will:**
  • *increase diuretic potency** and/or its duration of action?
  • *What will:
  • diminishes diuretic activity?***
A

Substitution with a:
LIPOPHYLIC GROUP** @ **C-3
INCREASES diuretic potency +/- Duration of action

  • any substitution of:*
  • *Methyl Group_ @ _N-4_ / _C-5_ / _C-8**
  • will DIMINISH diuretic activity*
50
Q

ADRs of Thiazides
HCTZ / Chlorthalidone
Metolazone / Indapamide

A
  • HYPO*
  • *K / Na** / Mg

HYPER
Calcium / Uricemia (Gout)
Glycemia / Cholesterol / LDL

51
Q

What is Essential for CAI’s Inhibitory Activity

SAR?

A
  • *UNSUBSTITUTED SULFAMOYL GROUP**
  • *(SO2NH2)**

+attached to a+

Aromatic** or **Heterocyclic Ring

52
Q

Which DIURETIC, based on MECHANISM OF ACTION?

inhibition of the:

Luminal Na+ / K+ / 2Cl- Transporter System

A 
**_LOOP_** or **High- Ceiling**
MOST POTENT class of diuretics

Furosemide / Bumetanide / Torsemide

Act on:
THICK ASCENDING LIMB

53
Q
A

methylxanthines

Diuretic effect is due to ability to increase renal blood flow and glomerular filtration rate.

•Theophylline is most effective

54
Q

Which DIURETIC acts on:

PROXIMAL TUBULE

A

CARBONIC ANHYDRASE INHIBITORS
Acetazolamide + Methazolamide
(Simple)
Dichlorfenamide + Dorzolamide
(meta)

OSMOTIC DIURETICS
Mannitol / Isosorbide / Sorbitol
also act on the DESCENDING LOOP

55
Q

Which DIURETIC, based on MECHANISM OF ACTION?

Inhibition of Na+ & Water RE-absorption by:

Blockade of Na+ Channel @ Luminal Membrane

A

POTASSIUM SPARING DIURETIC

TRIAMTERENE & AMILORIDE

Act on:
Late DISTAL TUBULE & COLLECTING DUCT

56
Q

Which Diuretic?

MoA:
Compete with WATER + CO2
for binding in the same active site
Of the Target Enzyme

A
  • *CAI’s**
  • *Carbonic Anhydrase**

Acetazolamide + Methazolamide
(Simple)
&
Dichlorfenamide + Dorzolamide
(meta)

Act on:
Proximal Tubule

57
Q

What occurs in the
DESCENDING LIMB?

Urine Formation

A

“Concentration of Luminal Fluid”
Osmotic Water Diffusion + Salts (active)

  • *WATER PERMEABLE**
  • water is RE-ABSORBED here*

Small amount of Na is ABSORBED
active transport –> into URINE

58
Q

Management of REFRACTORY EDEMA

A

ASSURE COMPIANCE
with Diuretic & NaCl Restriction
<1gm NaCl / day

  • if ALL FAILS:*
  • *Add Thiazide Diuretic**
  • CAUTION –> PROFOUND DIURESIS / severe e- / volume depletion*
  • only for SEVERE cases*
59
Q

Which DIURETIC?

A

Benzothiazide (Thiazide) Diuretics

The differences in
duration of action
are dictated mainly due to the
C-3 substituent.​

60
Q

Which DIURETIC?

A
  • *TRIAMTERENE**
  • *K+ Sparing Diuretic**

SELECTIVE SODIUM CHANNEL BLOCKER

Highly Basic

Triamterene metabolizes extensively by the liver enzymes (due to the presence of the phenyl ring)

61
Q

Which DIURETIC?

A

Methazolamide
SIMPLE heterocyclic sulfonamides

Carbonic Anhydrase Inhibitor

62
Q

What Diuretic is the only one that
DOES NOT ENTER THE TUBULAR LUMEN?

A

Aldosterone Antagonist
Spironolactone / Eplerenone
K+ Sparing Diuretic

Inhibit of the PRODUCTION of Na channels
VVV
reduce Na Reabsorption

63
Q

Which diuretic has been shown to:
high quality of evidence for
reducing morbidity and mortality for hypertension
but is the least used

A

CHLORTHALIDONE
Thiazide Diuretic
HCTZ is still used the most

Metolazone and Indapamide
are generally only used with Loop Diuretics for synergy

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